Rosie O'Donnell's mother died of cancer, and was buried on O'Donnell's eleventh birthday. Her parents had kept her illness from the family, leaving O'Donnell and her siblings unprepared for her death. Her father did not allow the children to attend their mother's funeral, and she says he "wasn't very available" after that. The children were raised mostly by each other, with help from neighbors and teachers. O'Donnell shielded herself from all this by developing a sharp sense of humor, and idealized fictional families from The Sound of Music to The Brady Bunch. In high school she was a good athlete, homecoming queen and class president, but says she never dated.

She started performing stand-up in local nightspots when she was 16, and while she was a struggling comic she worked in the catalogue department at Sears. In her early 20s she was a frequent competitor on TV's Star Search, and eventually joined the cast of Nell Carter's Gimme a Break as a wacky neighbor. She hosted Stand-Up Spotlight on VH1, and in 1992 she starred in Stand By Your Man, an offbeat comedy on Fox co-starring Melissa Gilbert as the "rich girl" to O'Donnell's "trailer trash". That sitcom bombed, just as O'Donnell's movie career took off.

She played the tart-tongued third-basewoman in A League of Their Own with Tom Hanks, Meg Ryan's best buddy in Sleepless in Seattle, Betty Rubble in the live-action Flintstones with John Goodman, and the acerbic Gina, who bluntly explained the difference between real and artificial beauty in Beautiful Girls with Timothy Hutton. She voiced a female gorilla in Disney's Tarzan, and in a little-seen but endearing performance she played a baseball-nutty nun in M. Night Shyamalan's Wide Awake.

Beginning in 1996 she hosted The Rosie O'Donnell Show, a pleasant change of pace from the trash-talk of Jenny Jones, Maury Povich, and Jerry Springer. It was highly rated, winning eleven Emmys, and O'Donnell won a twelfth for hosting the 1998 Tony telecast. Newsweek called O'Donnell the "Queen of Nice" for her talk show's simple, straightforward congeniality toward her guests and audience, often interviewing ordinary people and non-celebrity children. She also used her program to discuss issues she feels strongly about, including adoption, breast cancer awareness, and gun control.

In 1999, shortly after the Columbine massacre, she engaged in a heated exchange about gun control with Tom Selleck, who appeared on her show to promote his movie The Love Letter. After talking about the movie and taking a commercial break, O'Donnell came back asking Selleck, who had recently made a TV commercial for the National Rifle Association, to defend the NRA's position against regulating assault rifles. Selleck said he could not speak for the NRA, and O'Donnell replied that making the commercial made him a de facto spokesman for the NRA. Selleck said that they had agreed not to discuss gun control on camera, and O'Donnell, already a well-known liberal, became a much more despised character in ardent conservative circles.

She quit The Rosie O'Donnell Show of her own accord in 2002, saying she had earned enough money she would never again have to work, and that she wanted to spend more time with her family. Later that year she blasted several Hollywood stars -- without naming them -- for participating in the post-9/11 telethon and other charity events without making donations themselves. "In America," she said, "you should expect your millionaires to give millions -- especially if they're going to stand on TV and ask the peasants for pennies."

With her fortune, O'Donnell funds a New Jersey adoption agency, and has established the For All Kids Foundation, which has given more than $10-million for the social and intellectual development of disadvantaged children. She also runs Rosie’s Broadway Kids, which provides arts education for kids who live near New York's famed Broadway theater district but could otherwise never afford to experience it. Her R Family Vacations, a travel company that specializes in gay family vacations, was chronicled in the documentary All Aboard! Rosie's Family Cruise.

She was part of a business partnership that bought the floundering 122-year-old McCall's magazine in 2002, re-launching it as Rosie. Within months, though, O'Donnell and her partners had a very public falling out when it became apparent to her that she would not be allowed to exercise true editorial control of the magazine that carried her name. O'Donnell said the matter came to a head when, after interviewing Christopher Reeve and promising him that he would be featured on the magazine's cover, she was told that a cover photo of the paralyzed actor with his ventilator would be "too depressing". A messy lawsuit ensued, leading to a judge's verdict that neither side had proven its case, dismissing both suit and countersuit. "I believe this judge is a wise man," O'Donnell said leaving the courtroom. "I will not appeal the verdict." The magazine is no longer published, but O'Donnell writes and publishes her own weblog, unpretentious and full of unconcerned spelling errors.

On Broadway she played Betty Rizzo in Grease, the Cat in the Hat in Seussical, and Teyve's wife Golde in Fiddler on the Roof with Harvey Fierstein. She also produced the Broadway musical Taboo starring Boy George.

She says she figured out she was gay when she was 18. Through her early career she was routinely reported to be gay in the paparazzi press and never denied it, but she publicly came out in 2002 after she was unable to adopt her foster daughter because Florida state laws prohibit homosexuals and bisexuals from adopting. O'Donnell says she still considers Mia, the girl Florida wound not let her adopt, to be part of her family. In 2004, when San Francisco Mayor Gavin Newsom authorized gay marriage, O'Donnell and her longtime partner Kelli Carpenter were married there.

In 2006, O'Donnell returned to daytime TV when Katie Couric left Today to host the CBS Evening News, Meredith Vieira left The View to replace Couric, and O'Donnell joined The View, replacing Vieira. O'Donnell said she took the job because View matriarch Barbara Walters asked her to. "For you, I would do anything," she responded instantly. After joining the cast, O'Donnell made headlines almost immediately by commenting on the show that "Radical Christianity is just as threatening as radical Islam." She later made headlines by feuding with Donald Trump and calling for President Bush's impeachment. She left The View in 2007, then returned as a regular co-host in 2014 but left the program again in 2015.

Her brother, Daniel O'Donnell, has represented Manhattan as a New York Assemblyman since 2002, and is the first openly gay man in the New York State Assembly. Their great-grandmother's brother was actress Bridget Moynahan's great-grandfather, making O'Donnell and Moynahan third cousins.